Precocious puberty secondary to a mixed germ cell-sex cord-stromal tumor associated with an ovarian yolk sac tumor: a case report.

Abstract

Ovarian tumors are the least common cause of sexual precocity in girls. Mixed germ cell-sex cord-stromal tumors associated with a yolk sac tumor of the ovary are rare neoplasms, of which only a small number of well-documented cases have been described so far. Here, we report precocious puberty in a four-year-old Egyptian girl caused by a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary.
A four-year-old Egyptian girl was referred to our pediatric endocrinology unit for evaluation of bilateral breast budding, pubic hair and vaginal bleeding. On examination, we found that her breast enlargement and pubic hair were compatible with Tanner III. A thorough workup revealed a large mass in her right ovary. Magnetic resonance imaging ofher brain showed that her pituitary gland was normal. A hormonal assay revealed high levels of estradiol, 280 to 375pmol/L; progesterone, 5.3 nmol/L; testosterone 38.9 pg/mL; and androstenedione, 4.1 ng/mL. Her basal and stimulated levels of luteinizing hormone and follicle-stimulating hormone were low. Tumor markers levels were high, with a total inhibin of 1,069U/L and an alpha-fetoprotein of 987 μg/L. Her chromosomes were normal (46XX). Our patient underwent an explorative laparotomy and a solid tumor localized to her right ovary was identified. A right salpingo-oophorectomy was performed and the histopathological diagnosis was a mixed germ cell-sex cord-stromal tumorwith a yolk sac tumor of the ovary. Postoperatively, she was started on treatment with chemotherapy. Our patient is doing well without evidence of tumor recurrence or metastasis during eight months of postoperative follow-up.
Although a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary is a rare occurrence, it should be considered in the differential diagnosis for a prepubescent girl with an abdominal mass and precocious puberty.

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CASE REPORTOpen Access
Precocious puberty secondary to a mixed germ
cell-sex cord-stromal tumor associated with an
ovarian yolk sac tumor: a case report
Kotb Abbass Metwalley1*, Dalia Ahmed Elsers2, Hekma Saad Farghaly1, Hanaa Abdel-Lateif1and
Mohamed Abdel-Kader3
Abstract
Introduction: Ovarian tumors are the least common cause of sexual precocity in girls. Mixed germ cell-sex
cord-stromal tumors associated with a yolk sac tumor of the ovary are rare neoplasms, of which only a small number
of well-documented cases have been described so far. Here, we report precocious puberty in a four-year-old
Egyptian girl caused by a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary.
Case presentation: A four-year-old Egyptian girl was referred to our pediatric endocrinology unit for evaluation of
bilateral breast budding, pubic hair and vaginal bleeding. On examination, we found that her breast enlargement
and pubic hair were compatible with Tanner III. A thorough workup revealed a large mass in her right ovary.
Magnetic resonance imaging ofher brain showed that her pituitary gland was normal. A hormonal assay revealed
high levels of estradiol, 280 to 375pmol/L; progesterone, 5.3 nmol/L; testosterone 38.9 pg/mL; and androstenedione,
4.1 ng/mL. Her basal and stimulated levels of luteinizing hormone and follicle-stimulating hormone were low. Tumor
markers levels were high, with a total inhibin of 1,069U/L and an alpha-fetoprotein of 987 μg/L. Her chromosomes
were normal (46XX). Our patient underwent an explorative laparotomy and a solid tumor localized to her right ovary
was identified. A right salpingo-oophorectomy was performed and the histopathological diagnosis was a mixed
germ cell-sex cord-stromal tumorwith a yolk sac tumor of the ovary. Postoperatively, she was started on treatment
with chemotherapy. Our patient is doing well without evidence of tumor recurrence or metastasis during eight
months of postoperative follow-up.
Conclusion: Although a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary is a
rare occurrence, it should be considered in the differential diagnosis for a prepubescent girl with an abdominal mass
and precocious puberty.
Introduction
Precocious puberty in girls is defined by the develop-
ment of sexual characters before the age of eight years.
It is usually due to the premature activation of the
hypothalamic-pituitary-ovarian axis, defined as central
precocious puberty (CPP) [1]. It is rarely of ovarian or
adrenal origin. CPP in girls is idiopathic in the majority
of cases [2]. Ovarian tumors are the least common cause
of sexual precocity. Functional neoplasms of the ovary
are relatively infrequent and only 5% occur before
puberty [3]. Granulosa-theca cell tumors are the most
common ovarian tumors to cause precocious puberty in
girls [4]. Most ovarian tumors develop from one of three
sources: the germinal epithelium covering the urogenital
ridge; the underlying stromal elements of the urogenital
ridge; or germ cells from the yolk sac. The most com-
mon malignant germ cell tumors are dysgerminomas
(48%) and yolk-sac tumors (20%). Approximately 10% of
neoplasms are composed of a mixture of different histo-
logical types [5]. Tumors that contain an admixture of
germ cell and sex cord-stromal derivation include gona-
doblastoma and mixed germ cell-sex cord-stromal
tumor (MGCCST) -non gonadoblastoma type [6]. To
the best of our knowledge, an MGCCST with a yolk sac
* Correspondence: kotb72@yahoo.com
1Paediatric Endocrinology Unit, Department of Paediatrics, Faculty of
Medicine, Assiut University, Assiut, Egypt
Full list of author information is available at the end of the article
JOURNAL OF MEDICAL
CASE REPORTS
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tumor has not yet been described in Egypt. Here, we de-
scribe the clinical, histopathological and immunohistolo-
gical findings of a case of an MGCCST with a yolk sac
tumor that occurred in a four-year-old Egyptian girl pre-
senting with precocious puberty.
Case presentation
A four-year-old Egyptian girl was referred to our
pediatric endocrinology unit for evaluation of bilateral
breast budding and growth of pubic hair of four
months duration followed by two episodes of vaginal
spotting, initially noticed two weeks prior to her pres-
entation. Her previous medical history and birth his-
tory were unremarkable; there was no family history of
endocrinological disorders or precocious puberty. At
presentation, our patient was an alert, irritable child.
Her height was 115 cm (>97th percentile) and weight
20 kg (90th percentile). Her vital signs were normal.
She had normal ocular, thyroid and cardiorespiratory
examinations and no lymphadenopathy. Her breast
tissue was palpable and the contour of her nipples and
areolae was equivalent to Tanner stage III breast devel-
opment. Her pubic hair was coarse, pigmented and
distributed over her labia majora, equivalent to Tanner
stage III [7]. Inspection of her external genitalia
revealed estrogenized vulval mucosa with a clear vis-
cous discharge, and the clitoris was slightly enlarged.
An abdominal mass was palpable in her suprapubic
area, firm in consistency, not tender, with ill-defined
borders. There was no obvious ascities.
An initial ultrasonographic study of her abdomen and
pelvis revealed an enlarged uterus with prominent endo-
metrium and 7.8 cm×5.2 cm irregular, inhomogeneous
mass in the right adnexal region lying above her uterus
and crossing the midline. Her left ovary, adrenals, liver,
spleen and kidneys were normal. Computed tomography
imaging of her abdomen and pelvis confirmed the above
mentioned findings (Figure 1). Subsequent testing of her
brain by magnetic resonance imaging revealed a normal-
sized pituitary and infundibulum with a normal posterior
Figure 1 Computed tomography of the abdomen and pelvis shows a huge right ovarian mass.
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pituitary bright spot. An X-ray of her left hand and wrist
revealed a bone age of 5 years according to female stan-
dards [8].
Laboratory values of a complete blood count and
thyroid function tests were within the normal limits.
Serum concentrations of estradiol were in the range of
280 to 375 pmol/L (normal <73 for prepubertal child);
progesterone, 5.3 nmol/L (normal 0 to 1.3 nmol/L);
testosterone, 38.9 pg/mL (reference value 1 to 5.2 pg/mL);
androstenedione, 4.1 ng/mL (normal, 0.3 to 3.1 ng/mL);
and prolactin, 233 mIU/L (normal<460 mIU/L). Ba-
sal levels of luteinizing hormone (LH) and follicle-
stimulating hormone (FSH) were low (0.4 and 0.7 IU/L,
respectively), with no change in response to stimula-
tion by 100 mg of LH-releasing hormone intraven-
ously. Regarding tumor markers, the total inhibin level
was 1,069 U/L (normal <100 U/L for prepubertal child)
and the alpha fetoprotein levelwas 987 μg/L (normal 1
to 200 μg/L) while B human chorionic gonadotropin,
lactic dehydrogenase and alkaline phosphatase were
negative. Her chromosomes were normal (46XX). Our
patient underwent explorative laparotomy one week
after her initial presentation to our department; a solid
tumor localized to her right ovary was identified. A
right salpingo-oophorectomy was performed. Gross ex-
amination showed that the tumor mass measured about
10×7 cm in diameter. The mass was capsulated and its
outer surface was nodular with dilated congested blood
vessels. The cut section was solid and with multiple
cysts containing transparent thick material. The mass
was firm in consistency with friable areas. Its color
was yellow grayish with small dark areas of necrosis
(Figure 2). The histopathological report was an MGCCST
with a yolk sac tumor. The histological picture showed
the presence of the yolk sac tumor and a Sertoli-Leydig
cell tumor with intermediate differentiation (Figures 3, 4).
An immunohistochemical study of the tumor cells
showed diffuse positive staining for alpha-fetoprotein
(Figure 5) and focal areas of positive staining for in-
hibin (Figure 6).
Our patient’s postoperative period course was unre-
markable, although a short period of vaginal bleeding
was noted a few days after surgery. Pubic hair was lost
and her breasts became less prominent over the four
weeks following surgery. One month after surgery, she
was started on chemotherapy treatment with bleomycin,
etoposide and cisplatin (BEP regimen) every three weeks
for four cycles. Eight months after surgery and chemo-
therapy, she was tumor free on clinical examination and
radiography; her estradiol and testosterone levels had
decreased to 61 pmol/L and 3.1 pg/mL, respectively.
Our plan is to follow her up every three months for two
years then every six months for five years.
Figure 2 The cut section was solid with multiple cysts
containing transparent thick material. The mass was firm in
consistency with friable areas. Its color was yellow grayish with small
dark areas of necrosis.
Figure 3 Hematoxylin and eosin staining×40. Large polygonal
cells with abundant eosinophilic cytoplasm, and rounded
hyperchromatic nuclei growing in compact masses separated by
thin fibrous bands.
Figure 4 Hematoxylin and eosin staining×40. Primitive tumor
cells with vacuolated cytoplasm. Nuclei are rounded and
hyperchromatic, with prominent nucleoli.
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Discussion
Children with precocious puberty may be stressed be-
cause of physical and hormonal changes they are too
young to understand. Going through puberty early can
also be difficult for a child emotionally and socially.
Girls with precocious puberty may be confused or
embarrassed about physical changes, such as getting
their periods or having enlarged breasts well before any
of their peers. Not only that, but precocious puberty
could cause the child to become an object of adult sex-
ual interest [9]. Idiopathic CPP carries no increased risk
of mortality however, distinguishing between children
with idiopathic CPP and rare patients with a central ner-
vous system, adrenal or ovarian tumor is important be-
cause the latter group may be at risk for tumor-related
complications [10].
Our index case presented with a typical picture sug-
gestive of idiopathic CPP with maintenance of the
harmony (consonance) of normal puberty, that is,
breast and pubic hair development, vaginal bleeding,
growth acceleration and normal magnetic resonance
imaging of the brain. But, the presence of an ovarian
mass that was confirmed by computed tomography
and low levels of FSH and LH pointed to an ovarian
tumor as the sole cause of her precocious puberty.
Her advanced bone age and accelerated height were
seen because of tumor-derived estradiol. Advanced
bone age, especially if it has progressed beyond the
height age, serves as a nonspecific biomarker of abnor-
mal sex steroid production [11].
The endocrine effects of the tumor on our patient
were probably dependent upon the stromal compo-
nents and proportions of different elements. Tumors
containing both Sertoli and Leydig cells have variable
effects, depending partly upon the proportion of these
tumor elements and the degree of histologic differenti-
ation. Signs of androgen excess or overt virilization
occur in about half of patients with Sertoli-Leydig cell
tumors. As with the pure Leydig cell tumors, estro-
genic manifestations also occur. Patients with Sertoli-
Leydig cell tumors who have defeminizing or virilizing
clinical signs invariably have elevated blood testoster-
one levels [12]. In addition to testosterone, plasma
androstenedione and, less commonly, dehydroepian-
drosterone, are occasionally elevated [13]. Focal immu-
nohistochemical positivity for inhibin confirmed the
presence of the sex cord-stromal element. Total in-
hibin is a sensitive immunohistochemical marker of
ovarian sex cord-stromal tumors [14]. The high levels
ofestrogen accountfor
observed in this child and the build-up of the endo-
metrium [15]. We presume, based on the elevated
serum level of progesterone, that our patient's tumor
was intermittently releasing progesterone, causing her
vaginal bleeding [16]. The development of pubic hair
may be accounted for by the combination of elevated
testosterone, androstenedione and estrogen levels that
were most likely derived from the tumor [15].
An MGCCST with a yolk sac tumor of the ovary
should be differentiated clinically and pathologically from
a gonadoblastoma, described by Talerman in 1972
[17,18]. An MGCCST with a yolk sac tumor of the ovary
is very rare and there have been no reported cases in
Egypt. Most cases are found in infants and children
younger than 10 years, but rare cases occur in adults [19].
By comparison, a gonadoblastoma is a well-recognized
tumor that occurs almost exclusively in a patient with
abnormal gonadal development and a karyotype con-
taining Y-chromosome material [20]. The prognosis of
MGCCST with a yolk sac tumor of the ovary is depen-
dent on the response to therapy of the yolk sac tumor as
well as other components [21].
thebreast development
Figure 5 Tumor cells were positive for alpha-fetoprotein
staining, ×20.
Figure 6 Tumor cells showed focal positivity for inhibin alpha,
×40.
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Conclusion
Although in most of girls with precocious puberty, the
etiology is idiopathic, MGCCST with a yolk sac tumor of
the ovary should be considered in the differential diagno-
sis for a prepubescent girl with an abdominal mass.
Consent
Written informed consent was obtained from the
patient’s parents for publication of this case report and
any accompanying images. A copy of the written consent
is available for review by the Editor-in-Chief of this
journal.
Abbreviations
CPP: central precocious puberty; FSH: follicle-stimulating hormone;
LH: luteinizing hormone; MGCCST: mixed germ cell-sex cord-stromal tumor.
Competing interests
The authors declare that they have no competing interests.
Author details
1Paediatric Endocrinology Unit, Department of Paediatrics, Faculty of
Medicine, Assiut University, Assiut, Egypt.2Department of Pathology, Faculty
of Medicine, Assiut University, Assiut, Egypt.3Department of Pediatric
Surgery, Faculty of Medicine, Assiut University, Assiut, Egypt.
Authors’ contributions
KA carried out the patient diagnosis, investigation, follow-up, management
and writing of the manuscript. DS carried out the histopathological diagnosis
and writing of the manuscript. HS carried out the patient diagnosis, follow-
up, management and writing of the manuscript. HA carried out the patient
diagnosis and follow-up. MA carried out the excision of the tumor. All
authors read and approved the final manuscript.
Received: 14 February 2012 Accepted: 26 June 2012
Published: 26 June 2012
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doi:10.1186/1752-1947-6-162
Cite this article as: Metwalley et al.: Precocious puberty secondary to a
mixed germ cell-sex cord-stromal tumor associated with an ovarian yolk
sac tumor: a case report. Journal of Medical Case Reports 2012 6:162.
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